We propose to continue multi-disciplinary studies of the role of human papillomaviruses (HPV) in the etiology of anogenital cancers. The program incorporates epidemiologic and molecular biology approaches in the three projects, with support form four core functions including virology, pathology, biostatistics and administrative support. The nucleus of this effort is a series of case-control studies investigating the risk factor involved in squamous cell cervical cancer, anal cancer, vulvar cancer, vaginal cancer, adenocarcinoma of the cervix and penile cancers. The results from these studiers will increase the data base developed over the past thirteen years of this Program Project. Established polymerase chain reaction procedures for identification of HPV DNA together with the serologic tests developed in this program will continue to be used to establish virus infection and evidence of immune responses. A new focus on the occurrence of multiple cancers of the genital area is introduced, with the goal of establishing the primary and/or secondary state of tumors subsequent to an initial diagnosis. A group of women who have developed at least one additional primary anogenital cancer will be re- interviewed, together with appropriate controls, about exposures that may have contributed to the risk of a second primary tumor. Tissue and blood samples will be acquired for virus sequence, serologic and genetic testing. Determinations will be made of the uniqueness of the viral integration sites and the contribution of virus variants to the disease process. Studies of the roles of HLA genotypes in susceptibility to HPV- initiated cancer will be expanded. Comparative genome hybridization will continue to be used to id4entify loss or gain of chromosome regions and microarray methods used to investigate abnormal genes expression, with a particular focus of genes mapping on chromosomes 3, 5, and 20.